Libraries of 1-(sulfonyl)-n-phenylpyrrolidine-2-carboxamides for drug discovery

Abstract

New compounds are continually being sought for the treatment and prevention of disorders. The invention relates to 1-(sulfonyl)-N-phenyl-pyrrolidine 2-carboxamides which can be used in the search for, and identification of, new lead compounds that could modulate the functional activity of a biological target.

1 . A library of compounds wherein each member of said library is a compound of formula (I) 
       
         
           
           
               
               
           
         
         and the salts and stereoisomers thereof, wherein 
         R 1  is hydrogen, halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, and polyhaloC 1-6 alkoxy, aryl, Het; 
         R 2  is C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl or aryl; C 2-6 alkenyl optionally substituted with C 3-7 cycloalkyl or aryl; aryl; Het; or —NR 4a R 4b , wherein R 4a  and R 4b  are, each independently, C 1-6 alkyl, or R 4a  and R 4b  together with the nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring; 
         R 3  is C 1-6 alkylcarbonyl, C 1-6 alkyl substituted with aryl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl, C 1-6 alkyl substituted with Het; 
         n is one, two, three, four or five; 
         each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC l-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, and polyhaloC 1-6 alkoxy; and 
         each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C  1-6 alkoxy, C 1 -6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl. 
       
     
     
         2 . The library of compounds according to  claim 1 , wherein
 R 1  is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC l-6 alkyl, C 1-6 alkylcarbonyl, aryl; Het;   R 2  is C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl or aryl; C 2-6 alkenyl optionally substituted with C 3-7 cycloalkyl or aryl; aryl and Het;   R 3  is C 1-6 alkylcarbonyl, C 1-6 alkyl substituted with aryl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl, C 1-6 alkyl substituted with Het;   n is one, two or three;   each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or azido, mercapto, polyhaloC 1-6 alkyl, and polyhaloC 1-6 alkoxy; and   each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl.   
     
     
         3 . The library of compounds according to  claim 1 , wherein
 R 1  is hydrogen;   R 2  is aryl or Het;   R 3  is C 1-6 alkylcarbonyl, C 1-6 alkyl substituted with aryl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl, C 1-6 alkyl substituted with Het;   n is one;   each aryl as a group or part of a group is phenyl or naphthalenyl, each optionally substituted with two, three, four or five substituents selected from halo, amino, mono- or diC 1-6 alkylamino, and polyhaloC 1-6 alkyl; and   each Het as a group or part of a group is a monocyclic ring with 5 or 6 ring atoms or a bicyclic ring structure comprising a 6 membered ring fused to a 4, 5, or 6 membered ring; each of the rings being saturated, partially unsaturated, or completely unsaturated; at least one of the rings containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulphur; and any one of the rings being optionally substituted with one or two substituents each independently selected from the group consisting of halo and polyhaloC 1-6 alkyl.   
     
     
         4 . A pharmaceutical composition comprising a vehicle and as an active ingredient a therapeutic amount of a compound as defined in any of  claims 1  to  3 . 
     
     
         5 . A method of treatment comprising administering to an individual an effective amount of a compound having formula (I) or any subgroup of compounds of formula (I) according to any of  claims 1 - 3 , and the salts and stereoisomers thereof, for combating conditions associated with a disease or condition. 
     
     
         6 . The method according to  claim 5  in the treatment of diseases or conditions related to inflammation or coagulation. 
     
     
         7 . The method according to  claim 6  for treatment of a disease or condition in a warm-blooded animal. 
     
     
         8 . A process for preparing a library of compounds wherein each member of said library is a compound as claimed in any one of  claims 1 - 3 , said process comprising the step of
 a) reacting in a suitable medium compound of formula (II) with a compound of formula (III)   
       
         
           
           
               
               
           
         
         and 
         b) the further step of reacting in a suitable medium the product of step a) with R 3 -Y; 
         wherein 
         R 1 , R 2 , R 3 , and n have the same definition as provided in any one of  claims 1 - 3 ; 
         LG is an halogen atom, 
         Y is an activating group in coupling reactions or a leaving group in substitution reactions, 
         wherein, in substitution reactions Y is an halogen atom; 
         wherein in coupling reactions Y is an activated carboxyl derivative, or an active ester, 
         wherein the suitable medium of the reaction in step a) is a hydrous or anhydrous chlorinated solvent, anhydrous or non anhydrous polar aprotic solvent, at a temperature between 0° C. and 40° C., 
         wherein the suitable medium of the reaction in step b) is in the presence of an inorganic or organic base, at a temperature between −78° C. and 60° C., 
         and wherein the reaction solvent is a polar aprotic solvent. 
       
     
     
         9 . A compound of formula (IV) 
       
         
           
           
               
               
           
         
         and the salts and stereoisomers thereof, wherein 
         R 1  is hydrogen, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, and polyhaloC 1-6 alkoxy, aryl or Het; 
         R 5  is an amino protecting group, in the form of carbamate, urea-type derivative, amide, cyclic imide, alkyl, aryl, imine, enamine or heteroatom; and 
         n is one, two, three, four or five. 
       
     
     
         10 . A method of using the compounds of formula (IV) according to  claim 9  per se, the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, as synthetic intermediates in the preparation of a library of compounds wherein each member of said library is a compound formula (I). 
     
     
         11 . A method of using a library of compounds wherein each member of said library is a compound formula (IV) according to  claim 9 , the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, for being biologically and pharmaceutically explored in the search and identification of lead drugs in a drug discovering process. 
     
     
         12 . A compound of formula (V): 
       
         
           
           
               
               
           
         
         and the salts and stereoisomers thereof, wherein: 
         R 1  is hydrogen, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, and polyhaloC 1-6 alkoxy, aryl or Het; 
         R 5  is an amino protecting group, in the form of carbamate, urea-type derivative, amide, cyclic imide, alkyl, aryl, imine, enamine or heteroatom; 
         R 7  is a hydroxy activating group, preferably in the form of a sulfonate ester, para-toluenesulfonyl, methanesulfonyl or trifuloromethanesulfonyl; and 
         n is one, two, three, four or five. 
       
     
     
         13 . A method of using the compounds of formula (V) according to  claim 12  per se, the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, as synthetic intermediates in the preparation of a library of compounds wherein each member of said library is a corresponding compound of formula (I). 
     
     
         14 . A method of using a library of compounds wherein each member of said library is a compound formula (V) according to  claims 12 , the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, for being biologically and pharmaceutically explored in the search and identification of lead drugs in a drug discovering process. 
     
     
         15 . A compound of formula (VI) 
       
         
           
           
               
               
           
         
         and the salts and stereoisomers thereof, wherein 
         R 1  is hydrogen, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, and polyhaloC 1-6 alkoxy, aryl or Het; 
         R 5  is an amino protecting group, preferably carbamate, urea-type derivative, amide, cyclic imide, alkyl, aryl, imine, enamine or heteroatom; and 
         n is one, two, three, four or five. 
       
     
     
         16 . A method of using the compounds of formula (VI) according to  claim 15  per se, the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, as synthetic intermediates in the preparation of a library of compounds wherein each member of said library is a corresponding compound of formula (I). 
     
     
         17 . A method of using a library of compounds wherein each member of said library is a compound formula (VI) according to  claim 15  per se, the N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, for being biologically and pharmaceutically explored in the search and identification of lead drugs in a drug discovering process.